Cardiovascular disease (CVD) is the leading causes of death worldwide. One of the major gaps associated with the treatment of cardiovascular disease is the complexity of events that lead to its progression and the diverse forms of manifestation. Endothelial dysfunction, an early predictor of CVD, triggers a chronic inflammatory state that contributes to tissue fibrosis and development of atherosclerosis and associated events, such as myocardial infarction and stroke. Oxidant injury to the endothelium causes substantial damage that if not repaired may lead to senescence and endothelial dysfunction, increasing the chances of cardiovascular events, such as myocardial infarction and stroke. Vascular progenitors and endothelial cells play an essential role in the maintenance of vascular homeostasis, by directly contributing to the regenerative potential of the endothelial layer and preventing dysfunction. An essential mission for research in this area is to elucidate the effectors and modulators of vascular progenitors and endothelial cells stress susceptibility in order to maximize their protective and regenerative properties. Thus preventing endothelial dysfunction and reducing CVD-associated morbidity and mortality. Our long-term goal is to develop interventions to preserve vascular homeostasis, thus preventing endothelial dysfunction and associated CVD. The significance of our proposed studies relies on the identification of a novel molecular mechanism involved in vascular progenitors and endothelial response to stress that could be targeted in CVD prevention. We will address important questions related to a potential central mediator of vascular response to damage, by bridging our findings in vascular progenitors and mature endothelial cells. In our preliminary studies we show supporting evidence of the potential involvement of cMyc in protection of vascular progenitors and endothelial cells under stress conditions. Reduced cMyc expression in both cell types triggers the development of senescence, a cellular response to stress, and was associated with downregulation of Nrf2, a central transcription factor in the control of antioxidant protection. These findings support our central hypothesis that cMyc is required to protect vascular progenitors and endothelial cells from damage, preventing senescence and dysfunction. We designed 3 aims to test this hypothesis in vascular progenitors and endothelial cells. Aims 1 and 2 will be focused on cardiac vascular progenitor cells. We will determine the requirement of cMyc for cardiac vascular progenitor antioxidant protection, and the mechanisms involved in the control cMyc expression after exposure to stress. Aim 3 will be focused on endothelial cells. We will investigate the antioxidant role of cMyc in vascular endothelium. Completion of the proposed aims will define potential novel mechanism involved in vascular protection against oxidant damage and preservation of tissue homeostasis.